Methods and compositions using pde4 inhibitors for the treatment and management of cancers

Abstract

Methods of treating, preventing and/or managing hematological cancers are disclosed. Specific methods encompass the administration of a PDE4 inhibitor alone or in combination with a second active agent. The invention further relates to methods of treating leukemias and lymphomas which comprise the administration of a PDE4 inhibitor. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in methods of the invention are also disclosed.

1 . A method of treating chronic lymphocytic leukemia, which comprises administering to a patient having chronic lymphocytic leukemia a therapeutically effective amount of cyclopropanecarboxylic acid {2-[(1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide, which has the following structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         2 .- 12 . (canceled) 
     
     
         13 . The method of  claim 1 , further comprising the administration of a therapeutically effective amount of one or more additional active agents. 
     
     
         14 . The method of  claim 13 , wherein the additional active agent is selected from the group consisting of an alkylating agent, an adenosine analog, a glucocorticoid, a kinase inhibitor, a SYK inhibitor, a PDE3 inhibitor, a PDE7 inhibitor, doxorubicin, chlorambucil, vincristine, bendamustine, forskolin and rituximab. 
     
     
         15 . The method of  claim 13 , wherein the additional active agent is a PDE3 inhibitor. 
     
     
         16 . The method of  claim 13 , wherein the additional active agents are a PDE3 inhibitor and a PDE7 inhibitor. 
     
     
         17 . The method of  claim 13 , wherein the additional active agents are a cilostamide and a PDE7 inhibitor. 
     
     
         18 . The method of  claim 13 , wherein the additional active agent is rituximab. 
     
     
         19 . The method of  claim 1 , wherein the compound is enantiomerically pure. 
     
     
         20 . The method of  claim 1 , wherein the compound is administered in an amount of from about 1 to about 1,000 mg per day. 
     
     
         21 . The method of  claim 20 , wherein the compound is administered in an amount of about 10, 20, 25, 50, 100, 200 or 300 mg per day. 
     
     
         22 . The method of  claim 20 , wherein the compound is orally administered. 
     
     
         23 . The method of  claim 20 , wherein the compound is administered in a capsule or tablet. 
     
     
         24 . The method of  claim 23 , wherein the compound is administered in 50 mg or 100 mg of a capsule. 
     
     
         25 . The method of  claim 1 , wherein the chronic lymphocytic leukemia is relapsed, refractory or resistant to conventional therapy. 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . The method of  claim 1 , wherein the compound is administered for 21 days followed by seven days rest in a 28 day cycle.